The Impact of Carboxylesterase 1 ( CES1 ) in Personalized Antiplalet Therapy

羧酸酯酶 1 (CES1) 在个性化抗血小板治疗中的影响

基本信息

批准号：
9364969
负责人：
JOSHUA PATRICK LEWIS
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9364969
关键词：
Adverse event Affect Agonist Alleles Amino Acid Substitution Angiotensin-Converting Enzyme Inhibitors Antineoplastic Agents Antiplatelet Drugs Area Aspirin Bioinformatics Biological Blood Platelets CYP2C19 gene Carboxylesterase 1 Carboxylic Acids Cardiovascular system Catalytic Domain Clinical Coronary Arteriosclerosis Cross-Over Studies Data Development Enzymes Event Exons Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genotype Glutamic Acid Glycine Hemorrhage Heritability Hydrolysis Individual International Intervention Studies Investigation Medical Meta-Analysis Metabolism Methylphenidate Oseltamivir Outcome Participant Pathologic Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacotherapy Phenotype Physicians Platelet aggregation Positioning Attribute Prevention Prodrugs Randomized Recruitment Activity Recurrence Regimen Research Resistance Risk Single Nucleotide Polymorphism Sulfhydryl Compounds Testing Therapeutic Agents Time Translating United States National Institutes of Health Variant acute coronary syndrome alternative treatment base clinical application clopidogrel cost drug efficacy exome experience flexibility genetic information genetic variant genome sequencing inhibitor/antagonist insight inter-individual variation loss of function loss of function mutation novel percutaneous coronary intervention personalized medicine precision medicine prevent prospective receptor response serine esterase treatment strategy whole genome

项目摘要

PROJECT SUMMARY Medical management of coronary artery disease patients is most commonly achieved through dual antiplatelet therapy with aspirin and clopidogrel in order to reduce rates of recurrent atherothrombotic events. While clopidogrel is generally effective, substantial inter-individual variation in platelet response to this medication has been documented and patients who have altered clopidogrel response have increased risk of experiencing a cardiovascular event and would likely benefit from alternative treatment strategies. Previous investigations have shown that clopidogrel response is highly heritable; however, apart from CYP2C19*2, identification of genetic factors that are reproducibly associated with clopidogrel response has been limited. We have previously shown that a missense loss-of-function single nucleotide polymorphism (SNP) in exon 4 of carboxylesterase 1 (CES1) results in a catalytic site glycine (G)-to-glutamic acid (E) amino acid substitution at position 143 (G143E) and substantially impacts response to clopidogrel. Importantly, CES1 is the primary enzyme responsible for metabolizing the clopidogrel prodrug, its intermediate metabolite (2-oxo-clopidogrel), and the final bioactive thiol metabolite into biologically inactive carboxylic acid derivatives. Therefore, genetic variation affecting CES1 expression and/or activity is likely to be a critical determinant of clopidogrel efficacy. However, no investigation to date has characterized the impact of genetic variation in CES1 on clopidogrel response. In this proposal, our overall hypothesis is that comprehensive characterization of CES1 will unveil novel variants that significantly impact variable clopidogrel response and that use of an alternative P2Y12 receptor inhibitor (i.e. ticagrelor) will reverse the effect of these variants on on-treatment platelet function. We will test this hypothesis by leveraging existing exome and whole genome sequencing data in 5,000 individuals to bioinformatically prioritize genetic variation in CES1 and then assess the impact of these variants on clopidogrel efficacy in participants of the Pharmacogenomics of Anti-Platelet Intervention Study (N = 566) and International Clopidogrel Pharmacogenomics Consortium (N = 5,819). We will extend these findings by performing a prospective, randomized crossover study of clopidogrel (75 mg per day for 7 days) and ticagrelor (90 mg twice daily for 7 days) in healthy individuals by CES1 genotype (G143E and the most significantly associated variant identified in Specific Aim 1, 30 individuals per genotype group) in order to assess the interaction of genotype and drug choice on on-treatment agonist-stimulated platelet aggregation. These studies will contribute to our knowledge regarding the genetic underpinnings underlying clopidogrel resistance and will assess the impact of alternative antiplatelet therapy in individuals who are genetically predisposed to altered clopidogrel response. Understanding drug response variability and the development of novel treatment strategies is critical to enhance personalized medicine initiatives, optimize cardiovascular pharmacotherapy, and ultimately reduce adverse patient outcomes.

项目概要冠状动脉疾病患者的医疗管理最常通过双重方式实现使用阿司匹林和氯吡格雷进行抗血小板治疗，以降低复发性动脉粥样硬化血栓事件的发生率。虽然氯吡格雷通常有效，但血小板对此的反应存在显着的个体差异药物治疗已被记录，改变氯吡格雷反应的患者发生风险增加经历心血管事件，可能会受益于替代治疗策略。以前的研究表明，氯吡格雷反应具有高度遗传性；然而，除了 CYP2C19*2 之外，与氯吡格雷反应可重复相关的遗传因素的鉴定有限。我们之前已经证明，外显子 4 中存在错义功能丧失的单核苷酸多态性 (SNP) 羧酸酯酶 1 (CES1) 导致催化位点甘氨酸 (G) 至谷氨酸 (E) 的氨基酸取代位置 143 (G143E) 并显着影响对氯吡格雷的反应。重要的是，CES1 是主要的负责代谢氯吡格雷前药及其中间代谢物（2-氧代-氯吡格雷）的酶，最终的生物活性硫醇代谢物转化为生物非活性的羧酸衍生物。因此，遗传影响 CES1 表达和/或活性的变异可能是氯吡格雷疗效的关键决定因素。然而，迄今为止还没有研究表明 CES1 基因变异对氯吡格雷的影响回复。在本提案中，我们的总体假设是 CES1 的全面表征将揭示显着影响可变氯吡格雷反应的新变体以及替代 P2Y12 的使用受体抑制剂（即替格瑞洛）将逆转这些变异体对治疗中血小板功能的影响。我们将利用 5,000 名个体的现有外显子组和全基因组测序数据来检验这一假设以生物信息学的方式对 CES1 中的遗传变异进行优先排序，然后评估这些变异对氯吡格雷在抗血小板干预研究的药物基因组学参与者中的疗效 (N = 566) 和国际氯吡格雷药物基因组学联盟（N = 5,819）。我们将通过以下方式扩展这些发现对氯吡格雷（每天 75 毫克，持续 7 天）和替格瑞洛进行前瞻性、随机交叉研究（90 毫克，每天两次，持续 7 天）在健康个体中，按 CES1 基因型（G143E 和最显着的具体目标 1 中确定的相关变异，每个基因型组 30 个人），以便评估基因型和药物选择对治疗激动剂刺激血小板聚集的相互作用。这些研究将有助于我们了解氯吡格雷耐药性的遗传基础并将评估替代抗血小板疗法对遗传易感人群的影响改变氯吡格雷反应。了解药物反应变异性和新疗法的开发策略对于加强个性化医疗计划、优化心血管药物治疗、并最终减少患者的不良后果。